Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Alternative lengthening of telomeres in mammalian cells

Abstract

Some immortalized mammalian cell lines and tumors maintain or increase the overall length of their telomeres in the absence of telomerase activity by one or more mechanisms referred to as alternative lengthening of telomeres (ALT). Characteristics of human ALT cells include great heterogeneity of telomere size (ranging from undetectable to abnormally long) within individual cells, and ALT-associated PML bodies (APBs) that contain extrachromosomal telomeric DNA, telomere-specific binding proteins, and proteins involved in DNA recombination and replication. Activation of ALT during immortalization involves recessive mutations in genes that are as yet unidentified. Repressors of ALT activity are present in normal cells and some telomerase-positive cells. Telomere length dynamics in ALT cells suggest a recombinational mechanism. Inter-telomeric copying occurs, consistent with a mechanism in which single-stranded DNA at one telomere terminus invades another telomere and uses it as a copy template resulting in net increase in telomeric sequence. It is possible that t-loops, linear and/or circular extrachromosomal telomeric DNA, and the proteins found in APBs, may be involved in the mechanism. ALT and telomerase activity can co-exist within cultured cells, and within tumors. The existence of ALT adds some complexity to proposed uses of telomere-related parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomere maintenance.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 5
Figure 4

Similar content being viewed by others

Abbreviations

ALT:

alternative lengthening of telomeres

APB:

ALT-associated PML body

DSB:

double-strand break

ECTR:

extrachromosomal telomeric repeats

FISH:

fluorescent in situ hybridization

HPV:

human papillioma virus

HR:

homologous recombination

LFS:

Li-Fraumeni syndrome

PNB:

PML nuclear body

PD:

population doubling

SV40:

simion virus 40

TRD:

telomeric rapid deletion

TERT:

telomerase reverse transcriptase

TR:

telomerase RNA

TRF:

terminal restriction fragment.

References

  • Allshire RC, Dempster M, Hastie ND . 1989 Nucleic Acids Res. 17: 4611–4627

  • Aogi K, Kitahara K, Buley I, Backdahl M, Tahara H, Sugino T, Tarin D, Goodison S . 1998 Clin. Cancer Res. 4: 1965–1970

  • Aogi K, Kitahara K, Urquidi V, Tarin D, Goodison S . 1999 Clin. Cancer Res. 5: 2790–2797

  • Aogi K, Woodman A, Urquidi V, Mangham DC, Tarin D, Goodison S . 2000 Clin. Cancer Res. 6: 4776–4781

  • Baumann P, Cech TR . 2001 Science 292: 1171–1175

  • Bertrand P, Rouillard D, Boulet A, Levalois C, Soussi T, Lopez BS . 1997 Oncogene 14: 1117–1122

  • Biessmann H, Mason JM, Ferry K, d'Hulst M, Valgeirsdottir K, Traverse KL, Pardue M-L . 1990 Cell 61: 663–673

  • Bischof O, Kim S-H, Irving J, Beresten S, Ellis NA, Campisi J . 2001 J. Cell Biol. 153: 367–380

  • Bovée JVMG, van den Broek LJCM, Cleton-Jansen A-M, Hogendoorn PCW . 2001 J. Pathol. 193: 354–360

  • Brosh Jr RM, Karmakar P, Sommers JA, Yang Q, Wang XW, Spillare EA, Harris CC, Bohr VA . 2001 J. Biol. Chem. 276: 35093–35102

  • Brousset P, Chaouche N, Leprat F, Branet-Brousset F, Trouette H, Zenou RC, Merlio J-P, Delsol G . 1997 J. Clin. Endocrinol. Metab. 82: 4214–4216

  • Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR . 1997a Nat. Med. 3: 1271–1274

  • Bryan TM, Englezou A, Dunham MA, Reddel RR . 1998 Exp. Cell Res. 239: 370–378

  • Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR . 1995 EMBO J. 14: 4240–4248

  • Bryan TM, Marusic L, Bacchetti S, Namba M, Reddel RR . 1997b Hum. Mol. Genet. 6: 921–926

  • Bryan TM, Reddel RR . 1997 Eur. J. Cancer 33: 767–773

  • Buchhop S, Gibson MK, Wang XW, Wagner P, Stürzbecher H-W, Harris CC . 1997 Nucleic Acids Res. 25: 3868–3874

  • Bucholc M, Park Y, Lustig AJ . 2001 Mol. Cell. Biol. 21: 6559–6573

  • Cerone MA, Londono-Vallejo JA, Bacchetti S . 2001 Hum. Mol. Genet. 10: 1945–1952

  • Cheng A-J, Lin J-D, Chang T, Wang T-CV . 1998 Br. J. Cancer 77: 2177–2180

  • Cohen H, Sinclair DA . 2001 Proc. Natl. Acad. Sci. USA 98: 3174–3179

  • Cohen S, Regev A, Lavi S . 1997 Oncogene 14: 977–985

  • Colgin LM, Reddel RR . 1999 Curr. Opin. Genet. Dev. 9: 97–103

  • de Lange T . 1995 Telomere dynamics and genome instability in human cancer In Telomeres Blackburn EH, Greider CW (eds) Cold Spring Harbor Laboratory Press: New York pp 265–293

    Google Scholar 

  • de Lange T, Petrini JHJ . 2001 Cold Spring Harb. Symp. Quant. Biol. in press

  • de Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM, Varmus HE . 1990 Mol. Cell. Biol. 10: 518–527

  • Dessain SK, Yu H, Reddel RR, Beijersbergen RL, Weinberg RA . 2000 Cancer Res. 60: 537–541

  • Dunham MA, Neumann AA, Fasching CL, Reddel RR . 2000 Nat. Genet. 26: 447–450

  • Ford LP, Zou Y, Pongracz K, Gryaznov SM, Shay JW, Wright WE . 2001 J. Biol. Chem. 276: 32198–32203

  • Gollahon LS, Kraus E, Wu T-A, Yim SO, Strong LC, Shay JW, Tainsky MA . 1998 Oncogene 17: 709–717

  • Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T . 1999 Cell 97: 503–514

  • Grobelny JV, Godwin AK, Broccoli D . 2000 J. Cell Sci. 113: 4577–4585

  • Grobelny JV, Kulp-McEliece M, Broccoli D . 2001 Hum. Mol. Genet. 10: 1953–1961

  • Guiducci C, Cerone MA, Bacchetti S . 2001 Oncogene 20: 714–725

  • Hande MP, Balajee AS, Tchirkov A, Wynshaw-Boris A, Lansdorp PM . 2001 Hum. Mol. Genet. 10: 519–528

  • Hande MP, Samper E, Lansdorp P, Blasco MA . 1999 J. Cell Biol. 144: 589–601

  • Harley CB . 1997 Ciba Found. Symp. 211: 129–144

  • Haugen BR, Nawaz S, Markham N, Hashizumi T, Shroyer AL, Werness B, Shroyer KR . 1997 Thyroid 7: 337–342

  • Henderson S, Allsopp R, Spector D, Wang S-S, Harley C . 1996 J. Cell Biol. 134: 1–12

  • Herrera E, Martínez C, Blasco MA . 2000 EMBO J. 19: 472–481

  • Hickson ID, Davies SL, Li J-L, Levitt NC, Mohaghegh P, North PS, Wu L . 2001 Biochem. Soc. Trans. 29: 201–204

  • Hiraga S, Ohnishi T, Izumoto S, Miyahara E, Kanemura Y, Matsumura H, Arita N . 1998 Cancer Res. 58: 2117–2125

  • Hoare SF, Bryce LA, Wisman GBA, Burns S, Going JJ, Van der Zee AGJ, Keith WN . 2001 Cancer Res. 61: 27–32

  • Hodges M, Tissot C, Howe K, Grimwade D, Freemont PS . 1998 Am. J. Hum. Genet. 63: 297–304

  • Hu P, Beresten SF, van Brabant AJ, Ye T-Z, Pandolfi P-P, Johnson FB, Guarente L, Ellis NA . 2001 Hum. Mol. Genet. 10: 1287–1298

  • Huang P-H, Pryde FE, Lester D, Maddison RL, Borts RH, Hickson ID, Louis EJ . 2001 Curr. Biol. 11: 125–129

  • Johnson FB, Marciniak RA, McVey M, Stewart SA, Hahn WC, Guarente L . 2001 EMBO J. 20: 905–913

  • Kammori M, Takubo K, Nakamura K, Furugouri E, Endo H, Kanauchi H, Mimura Y, Kaminishi M . 2000 Cancer Lett. 159: 175–181

  • Karow JK, Wu L, Hickson ID . 2000 Curr. Opin. Genet. Dev. 10: 32–38

  • Katoh M, Katoh M, Kameyama M, Kugoh H, Shimizu M, Oshimura M . 1998 Mol. Carcinog. 21: 17–25

  • Kilian A, Bowtell DDL, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR, Jefferson RA . 1997 Hum. Mol. Genet. 6: 2011–2019

  • Kishi S, Wulf G, Nakamura M, Lu KP . 2001 Oncogene 20: 1497–1508

  • Kreuzer KN . 2000 Trends Biochem. Sci. 25: 165–173

  • Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honoré N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, De Thé H . 2001 J. Exp. Med. 193: 1361–1372

  • Lansdorp PM, Poon S, Chavez E, Dragowska V, Zijlmans M, Bryan T, Reddel R, Egholm M, Bacchetti S, Martens U . 1997 Ciba Found. Symp. 211: 209–218

  • Le S, Moore JK, Haber JE, Greider CW . 1999 Genetics 152: 143–152

  • Li B, Lustig AJ . 1996 Genes Dev. 10: 1310–1326

  • Lipps HJ, Feiler S, Azorin F . 1998 J. Mol. Biol. 283: 1–7

  • Liu Y, Maizels N . 2000 EMBO rep. 1: 85–90

  • Lo CY, Lam KY, Chan KT, Luk JM . 1999 Thyroid 9: 1215–1220

  • Lombard DB, Guarente L . 2000 Cancer Res. 60: 2331–2334

  • Ludérus ME, van Steensel B, Chong L, Sibon OCM, Cremers FFM, de Lange T . 1996 J. Cell Biol. 135: 867–881

  • Lundblad V, Blackburn EH . 1993 Cell 73: 347–360

  • Martens UM, Chavez EA, Poon SS, Schmoor C, Lansdorp PM . 2000 Exp. Cell Res. 256: 291–299

  • Matthews P, Jones CJ, Skinner J, Haughton M, de Micco C, Wynford-Thomas D . 2001 J. Pathol. 194: 183–193

  • Maul GG, Negorev D, Bell P, Ishov AM . 2000 J. Struct. Biol. 129: 278–287

  • McEachern MJ . 2001 Recombinational telomere elongation in the yeast K. lactis In Telomeres and telomerases: cancer and biology Krupp G (ed) Landes Bioscience: Georgetown, TX, USA in press

    Google Scholar 

  • McEachern MJ, Blackburn EH . 1996 Genes Dev. 10: 1822–1834

  • Mehle C, Piatyszek MA, Ljungberg B, Shay JW, Roos G . 1996 Oncogene 13: 161–166

  • Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ, Taylor AMR . 1996 Nat. Genet. 13: 350–353

  • Montalto MC, Phillips JS, Ray FA . 1999 J. Cell. Physiol. 180: 46–52

  • Muñoz-Jordán JL, Cross GAM, de Lange T, Griffith JD . 2001 EMBO J. 20: 579–588

  • Murnane JP, Sabatier L, Marder BA, Morgan WF . 1994 EMBO J. 13: 4953–4962

  • Murti KG, Prescott DM . 1999 Proc. Natl. Acad. Sci. USA 96: 14436–14439

  • Nakabayashi K, Ogata T, Fujii M, Tahara H, Ide T, Wadhwa R, Kaul SC, Mitsui Y, Ayusawa D . 1997 Exp. Cell Res. 235: 345–353

  • Niida H, Shinkai Y, Hande MP, Matsumoto T, Takehara S, Tachibana M, Oshimura M, Lansdorp PM, Furuichi Y . 2000 Mol. Cell. Biol. 20: 4115–4127

  • Noma K, Allis CD, Grewal SIS . 2001 Science 293: 1150–1155

  • Nosek J, Tomáska L, Fukuhara H, Suyama Y, Kovác L . 1998 Trends Genet. 14: 184–188

  • Ogata T, Ayusawa D, Namba M, Takahashi E, Oshimura M, Oishi M . 1993 Mol. Cell. Biol. 13: 6036–6043

  • Ogata T, Oshimura M, Namba M, Fujii M, Oishi M, Ayusawa D . 1995 Jpn. J. Cancer Res. 86: 35–40

  • Ogino H, Nakabayashi K, Suzuki M, Takahashi E-I, Fujii M, Suzuki T, Ayusawa D . 1998 Biochem. Biophys. Res. Commun. 248: 223–227

  • Okabe J, Eguchi A, Masago A, Hayakawa T, Nakanishi M . 2000 Hum. Mol. Genet. 9: 2639–2650

  • Okayasu I, Osakabe T, Fujiwara M, Fukuda H, Kato M, Oshimura M . 1997 Jpn. J. Cancer Res. 88: 965–970

  • Opitz OG, Suliman Y, Hahn WC, Harada H, Blum HE, Rustgi AK . 2001 J. Clin. Invest. 108: 725–732

  • Park KH, Rha SY, Kim CH, Kim TS, Yoo NC, Kim JH, Roh JK, Noh SH, Min JS, Lee KS, Kim BS, Chung HC . 1998 Int. J. Oncol. 13: 489–495

  • Park PU, Defossez P-A, Guarente L . 1999 Mol. Cell. Biol. 19: 3848–3856

  • Pereira-Smith OM, Smith JR . 1983 Science 221: 964–966

  • Pereira-Smith OM, Smith JR . 1988 Proc. Natl. Acad. Sci. USA 85: 6042–6046

  • Perrem K, Bryan TM, Englezou A, Hackl T, Moy EL, Reddel RR . 1999 Oncogene 18: 3383–3390

  • Perrem K, Colgin LM, Neumann AA, Yeager TR, Reddel RR . 2001 Mol. Cell. Biol. 21: 3862–3875

  • Reddel RR . 2000 Carcinogenesis 21: 477–484

  • Reddel RR, Bryan TM, Colgin LM, Perrem KT, Yeager TR . 2001 Radiat. Res. 155: 194–200

  • Reddel RR, Bryan TM, Murnane JP . 1997 Biochemistry (Mosc) 62: 1254–1262

  • Regev A, Cohen S, Cohen E, Bar-Am I, Lavi S . 1998 Oncogene 17: 3455–3461

  • Rizki A, Lundblad V . 2001 Nature 411: 713–716

  • Rogan EM, Bryan TM, Hukku B, Maclean K, Chang ACM, Moy EL, Englezou A, Warneford SG, Dalla-Pozza L, Reddel RR . 1995 Mol. Cell. Biol. 15: 4745–4753

  • Roth CW, Kobeski F, Walter MF, Biessmann H . 1997 Mol. Cell. Biol. 17: 5176–5183

  • Ruggero D, Wang Z-G, Pandolfi PP . 2000 BioEssays 22: 827–835

  • Saji M, Westra WH, Chen H, Umbricht CB, Tuttle RM, Box MF, Udelsman R, Sukumar S, Zeiger MA . 1997 Surgery 122: 1137–1140

  • Saji M, Xydas S, Westra WH, Liang C-K, Clark DP, Udelsman R, Umbricht CB, Sukumar S, Zeiger MA . 1999 Clin. Cancer Res. 5: 1483–1489

  • Scheel C, Schaefer K-L, Jauch A, Keller M, Wai D, Brinkschmidt C, van Valen F, Boecker W, Dockhorn-Dworniczak B, Poremba C . 2001 Oncogene 20: 3835–3844

  • Schneider-Stock R, Epplen JT, Walter H, Radig K, Rys J, Epplen C, Hoang-Vu C, Niezabitowski A, Roessner A . 1999 Mol. Carcinog. 24: 144–151

  • Shay JW, Bacchetti S . 1997 Eur. J. Cancer 33: 787–791

  • Shay JW, Tomlinson G, Piatyszek MA, Gollahon LS . 1995 Mol. Cell. Biol. 15: 425–432

  • Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ . 1996 Genomics 36: 271–279

  • Shore D . 2001 Curr. Opin. Genet. Dev. 11: 189–198

  • Sinclair DA, Guarente L . 1997 Cell 91: 1033–1042

  • Small MB, Hubbard K, Pardinas JR, Marcus AM, Dhanaraj SN, Sethi KA . 1996 J. Cell. Physiol. 168: 727–736

  • Smith J, Zou H, Rothstein R . 2000 Biochimie 82: 71–78

  • Sprung CN, Bryan TM, Reddel RR, Murnane JP . 1997 Mutat. Res. 379: 177–184

  • Strahl C, Blackburn EH . 1996 Mol. Cell. Biol. 16: 53–65

  • Sugawara N, Ivanov EL, Fishman-Lobell J, Ray BL, Wu X, Haber JE . 1995 Nature 373: 84–86

  • Sugihara S, Mihara K, Marunouchi T, Inoue H, Namba M . 1996 Hum. Genet. 97: 1–6

  • Sugimoto M, Ide T, Goto M, Furuichi Y . 1999 Mech. Ageing Dev. 107: 51–60

  • Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, Yamaguchi-Iwai Y, Shinohara A, Takeda S . 1998 EMBO J. 17: 5497–5508

  • Tanaka K, Nishide J, Okazaki K, Kato H, Niwa O, Nakagawa T, Matsuda H, Kawamukai M, Murakami Y . 1999 Mol. Cell. Biol. 19: 8660–8672

  • Teng S-C, Chang J, McCowan B, Zakian VA . 2000 Mol. Cell 6: 947–952

  • Teng S-C, Zakian VA . 1999 Mol. Cell. Biol. 19: 8083–8093

  • Thompson LH, Schild D . 2001 Mutat. Res. 477: 131–153

  • Tokutake Y, Matsumoto T, Watanabe T, Maeda S, Tahara H, Sakamoto S, Niida H, Sugimoto M, Ide T, Furuichi Y . 1998 Biochem. Biophys. Res. Commun. 247: 765–772

  • Tomaska L, Nosek J, Makhov AM, Pastorakova A, Griffith JD . 2000 Nucleic Acids Res. 28: 4479–4487

  • Tommerup H, Dousmanis A, de Lange T . 1994 Mol. Cell. Biol. 14: 5777–5785

  • Tong W-M, Hande MP, Lansdorp PM, Wang Z-Q . 2001 Mol. Cell. Biol. 21: 4046–4054

  • Tsutsui T, Fujino T, Kodama S, Tainsky MA, Boyd J, Barrett JC . 1995 Carcinogenesis 16: 25–34

  • Tsutsui T, Tanaka Y, Matsudo Y, Hasegawa K, Fujino T, Kodama S, Barrett JC . 1997 Mol. Carcinog. 18: 7–18

  • Vogt M, Haggblom C, Yeargin J, Christiansen-Weber T, Haas M . 1998 Cell Growth Differ. 9: 139–146

  • Wahl GM . 1989 Cancer Res. 49: 1333–1340

  • Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC . 2001 J. Biol. Chem. 276: 32948–32955

  • Wen J, Cong Y-S, Bacchetti S . 1998 Hum. Mol. Genet. 7: 1137–1141

  • Whitaker NJ, Bryan TM, Bonnefin P, Chang ACM, Musgrove EA, Braithwaite AW, Reddel RR . 1995 Oncogene 11: 971–976

  • Wold MS . 1997 Annu. Rev. Biochem. 66: 61–92

  • Wotton D, Shore D . 1997 Genes Dev. 11: 748–760

  • Wright WE, Tesmer VM, Huffman KE, Levene SD, Shay JW . 1997 Genes Dev. 11: 2801–2809

  • Wu G, Lee W-H, Chen P-L . 2000 J. Biol. Chem. 275: 30618–30622

  • Wu L, Davies SL, Levitt NC, Hickson ID . 2001 J. Biol. Chem. 276: 19375–19381

  • Xia SJ, Shammas MA, Shmookler Reis RJ . 1996 Mutat. Res. 364: 1–11

  • Yan P, Coindre J-M, Benhattar J, Bosman FT, Guillou L . 1999 Cancer Res. 59: 3166–3170

  • Yankiwski V, Marciniak RA, Guarente L, Neff NF . 2000 Proc. Natl. Acad. Sci. USA 97: 5214–5219

  • Yashima K, Vuitch F, Gazdar AF, Fahey III TJ . 1997 Surgery 122: 1141–1145

  • Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR . 1999 Cancer Res. 59: 4175–4179

  • Yeh ETH, Gong L, Kamitani T . 2000 Gene 248: 1–14

  • Yoo J, Robinson RA . 2000 Arch. Pathol. Lab. Med. 124: 393–397

  • Zhong S, Salomoni P, Pandolfi PP . 2000 Nat. Cell Biol. 2: E85–E90

  • Zhu X-D, Küster B, Mann M, Petrini JHJ, de Lange T . 2000 Nat. Genet. 25: 347–352

Download references

Acknowledgements

The authors thank Clare Fasching for comments on the manuscript. Work in the authors' laboratory is supported by Cancer Council NSW and the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roger R Reddel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Henson, J., Neumann, A., Yeager, T. et al. Alternative lengthening of telomeres in mammalian cells. Oncogene 21, 598–610 (2002). https://doi.org/10.1038/sj.onc.1205058

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205058

Keywords

This article is cited by

Search

Quick links